Enhancement of activity and/or duration of action of soft anti-inflammatory steroids for topical or other local application

ABSTRACT

Methods and compositions for enhancing the activity and/or duration of action of loteprednol etabonate and other soft anti-inflammatory steroids of the haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate type and the corresponding Δ 1,4 -compounds are described. The enhancing agents have the formula: 
     
       
         
         
             
             
         
       
     
     wherein R is H or C 1 -C 4  alkyl; Z 1  is carbonyl or β-hydroxymethylene; X 1  is —O— or —S—; R 5  is —OH, —OR 6 , —OCOOR 6  or —OCOR 7  wherein R 6  is C 1 -C 4  alkyl and R 7  is C 1 -C 4  alkyl, fluoromethyl or chloromethyl; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; with the proviso that when R is C 1 -C 4  alkyl, then R 5  is —OH.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of prior copending application Ser. No.10/868,966, filed Jun. 17, 2004, now allowed, which claims the benefitof U.S. Provisional Patent Application No. 60/479,496, filed Jun. 19,2003, both incorporated by reference herein in their entireties andrelied upon.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The invention relates to enhancing the activity and/or the duration ofaction of soft anti-inflammatory steroids for topical or other localapplication.

2. Background Art

Topical or other local application of potent glucocorticoids can producesevere toxic effects such as Cushingoid features, pituitary-adrenalsuppression, skin atrophy, immunosuppression, weight gain and inhibitionof wound healing. Other kinds of toxic responses, including allergiesand cataracts, have resulted from long term use of drugs of this type.

Ophthalmic application of glucocorticosteroids presents additionalproblems. The protective mechanisms built into the eye allow only smallamounts of doses applied to the eye to reach the target sites within theeye; generally, over 90 percent of the total dose will find its way intothe general circulation. This in turn leads to serious systemic sideeffects of the type described above. Moreover, there is a more seriousand specific side effect when these drugs are used in the eye, which isan increase in intraocular pressure (IOP). Corticosteroid-inducedchronic or acute glaucoma has in fact been reported since the early1960's. Generally, the corticosteroid is needed only topically tocontrol the inflammation. However, the absorbed steroid is responsiblefor the serious side effects noted above. It is believed that the effectof the corticosteroid on the aqueous outflow pathway and adjacent tissueglycosaminoglycans (GAG's) is important in the development ofglucocorticoid-induced ocular hypertension.

The natural glucocorticosteroids and many of their marketed derivativesare Δ⁴ and Δ^(1,4) pregnenes having 21-hydroxy substituents. There are,however, a number of anti-inflammatory Δ⁴ and Δ^(1,4) androstenesdescribed in the literature; note, for example, British PatentSpecification No. 1,384,372; Phillipps et al. U.S. Pat. No. 3,828,080and Kalvoda et al. U.S. Pat. No. 4,285,937.

In recent years, soft steroids have been developed in an effort toprovide compounds having potent anti-inflammatory activity with minimalsystemic activity. One series of soft steroids which is described ashaving potent anti-inflammatory activity with minimal systemic activityconsists of the 17α-carbonates of Bodor U.S. Pat. No. 4,996,335. Thesecompounds include as preferred embodiments haloalkyl17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylates andthe corresponding Δ^(1,4) compounds, optionally bearing 6α- and/or9α-fluorine and 16α- or 16β-methyl substituents. One of these compoundsis chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate,also known as loteprednol etabonate. Loteprednol etabonate is presentlymarketed in the United States by Bausch & Lomb Pharmaceuticals, Inc. asAlrex® and Lotemax® for ophthalmic use. Other uses of loteprednoletabonate are currently in clinical trials.

Despite the development of steroids having less systemic toxicity,however, there is a serious need for improvement in topical and otherlocal applications. The newer, less toxic, locally/topically activecompounds are more expensive to synthesize than the long-establishedcompounds. Moreover, the most potent anti-inflammatory steroids arethose which have substitution at the 6, 9 and/or 16-positions and thusalso not only are farthest removed structurally from the naturalcorticosteroids but also have the greatest toxicity. Thus, there is aneed for enhancing the activity or duration of action or both of the17α-carbonate type soft androstenes which lack the 6-, 9- and/or16-substitution pattern. Further, it would be desirable to allow thesesteroids to undergo easier metabolism and concentrate them at thedesired site of action.

One of the major, inactive metabolites of hydrocortisone is cortienicacid, i.e. 11β, 17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid.Cortienic acid and the corresponding Δ^(1,4) acid have been previouslydescribed as synthetic intermediates useful in the preparation of thesoft steroids described in Bodor U.S. Pat. Nos. 4,710,495 and 4,996,335.The 17β-methyl, ethyl and isopropyl esters of Δ¹-cortienic acid havebeen described as putative inactive metabolites of the anti-inflammatoryandrostene derivatives of WO 97/42214 and Bodor U.S. Pat. No. 5,981,517.The '517 patent also describes the use of Δ¹-cortienic acid as acompetitor (with [3H]-triamcinolone acetonide as a tracer) for in vitroreceptor binding studies of the androstene derivatives of that patentand notes similar studies of loteprednol etabonate. Druzgala et al., J.Steroid Biochem. Molc. Biol., Vol. 38, No. 2, pp.149-154 (1991), reportsearlier in vitro receptor binding studies of loteprednol etabonate andtwo putative metabolites, Δ¹-cortienic acid and the corresponding17α-ethyl carbonate, in a medium containing 10⁻⁵M cortienic acid ascompetitor, along with [3H]-triamcinolone acetonide as tracer. Druzgalaet al. further note that loteprednol itself is intrinsically active,whereas the putative metabolites are indeed inactive. Neither theseacids nor their esters have been previously suggested for use inpharmaceutical compositions for the treatment of inflammation becausethey are not themselves active as anti-inflammatory agents.

SUMMARY AND OBJECTS OF THE INVENTION

It has now been found that cortienic acid and related compounds enhancethe topical or other local activity or duration of action of selectedsoft anti-inflammatory steroids.

Thus, in one aspect, the present invention provides a pharmaceuticalcomposition of matter comprising:

-   (1) a combined synergistic anti-inflammatory effective amount of:    -   (a) a compound having the formula:

wherein:

-   R₁ is C₁-C₇ alkyl;-   Z is carbonyl or β-hydroxymethylene;-   X is Cl or F;-   and the dotted line in ring A indicates that the 1,2-linkage is    saturated or unsaturated;-   and    -   (b) a compound having the formula:

wherein:

-   R is H or C₁-C₄ alkyl;-   Z₁ is carbonyl or β-hydroxymethylene;-   X₁ is —O— or —S—;-   R₅ is —OH, —OR₆, —OCOOR₆ or —OCOR₇ wherein R₆ is C₁-C₄ alkyl, and R₇    is C₁-C₄ alkyl, fluoromethyl or chloromethyl;-   and the dotted line is defined as above;-   with the proviso that when R is C₁-C₄ alkyl, then R₅ is —OH;-   the amount of compound of formula (II) being sufficient to enhance    the anti-inflammatory activity or duration of action, or both, of    said compound of formula (I), and-   (2) a non-toxic, pharmaceutically acceptable carrier therefore    suitable for topical or other local application.

In another aspect, the invention provides a combination comprising (a)and (b) above, in a combined synergistic anti-inflammatory effectiveamount, the amount of (b) being sufficient to enhance theanti-inflammatory activity or duration of action, or both, of (a).

In another aspect, the invention provides the compositions andcombinations as described above but with the proviso that[3H]-triamcinolone acetonide is not present in the composition orcombination, or with the proviso that the composition or combinationcomprises (a) and (b) above as the only steroids in the composition; orwith the proviso that the molar ratio of the compound of formula (II) tothe compound of formula (I) is from about 5:1 to about 0.2:1 (preferablyfrom about 0.5:1 to 1:1). The condition of one of these provisos isapplicable when the compound of formula (II) has been previouslyemployed in in vitro testing of the active compound, that is when theactive compound is loteprednol etabonate and the compound of formula(II) is cortienic acid or Δ¹-cortienic acid. Of course, the compositionsand combinations whose definitions include one of the provisos, but inwhich the active compound is other than loteprednol etabonate and/or theenhancer is other than cortienic acid or Δ¹-cortienic acid, includepreferred aspects of the invention, in particular the provisos whichspecify the absence of the radiolabelled steroid and the use of therecited ratio.

In still a further aspect, the compositions described above areophthalmic compositions and the carrier is a non-toxic, ophthalmicallyacceptable one.

In another aspect, the present invention provides a pharmaceuticalcomposition of matter comprising:

-   (a) an anti-inflammatory effective amount of a compound having    formula (I) as defined above;-   (b) an amount of a compound of formula (II) as defined above    sufficient to enhance the anti-inflammatory activity or duration of    action, or both, of said compound of formula (I); and-   (c) a non-toxic, pharmaceutically acceptable carrier suitable for    topical or other local application;-   with the optional provisos indicated hereinabove.

In yet another aspect, the invention provides a combination comprising:

-   (a) an anti-inflammatory effective amount of a compound having    formula (I) as defined above; and-   (b) an amount of a compound of formula (II) as defined above    sufficient to enhance the anti-inflammatory activity or duration of    action, or both, of said compound of formula (I).

In a further aspect of the invention, there is provided a composition asdefined in the preceding paragraph in which the composition isophthalmic and the carrier is a non-toxic, ophthalmically acceptableone.

In yet another aspect, the present invention provides a method forenhancing the anti-inflammatory activity or duration of action, or both,of a compound having formula (I) as defined above following topical orother local administration of said compound to a warm-blooded animal toalleviate a topical or other localized (e.g. ophthalmic) inflammatoryresponse, said method comprising topically or otherwise locally (e.g.ophthalmically) co-administering said compound to said animal with asynergistically effective amount of a compound having formula (II) asdefined above, the amount of the compound of formula (II) beingsufficient to enhance the anti-inflammatory activity or duration ofaction, or both, of said compound of formula (I). Preferably, thecompounds are co-administered in the form of one of the compositions ofthe invention defined above.

In still another aspect, the present invention provides a method fordecreasing the in vivo transcortin binding of an anti-inflammatorysteroid which binds to transcortin, and which is a compound havingformula (I) as defined above, and for thus enhancing theanti-inflammatory activity or duration of action, or both, of saidsteroid following topical or other local administration of said steroidto a warm-blooded animal to alleviate a topical or other localized (e.g.ophthalmic) inflammatory response, said method comprising topically orotherwise locally (e.g. ophthalmically) co-administering said steroid tosaid animal with an amount of a compound having formula (II) above whichis effective to decrease the in vivo transcortin binding of saidsteroid. Again, the compounds are preferably co-administered in the formof one of the compositions of the invention defined above.

In a further aspect, there is provided a method for enhancing thehydrolytic stability of a compound of formula (I) by combining therewitha carboxylic acid of formula (II), that is, a compound of formula (II)wherein X₁R is OH and the other structural variables are defined asabove.

Thus, the present invention provides a new use of a compound of formula(II) in the preparation of a medicament for treatment of topical andother local inflammation, such as for treatment of ophthalmicinflammation; the compound of formula (II), while not itself havinguseful anti-inflammatory activity, is employed in accord with thepresent invention to enhance the activity of an anti-inflammatorysteroid having transcortin binding activity, and having formula (I)above, by combining the compound of formula (II) with the active steroidof formula (I) in one of the compositions defined above.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the instant specification and claims, the followingdefinitions and general statements are applicable.

The patents, published applications, and scientific literature referredto herein establish the knowledge of those with skill in the art and arehereby incorporated by reference in their entirety to the same extent asif each was specifically and individually indicated to be incorporatedby reference. Any conflict between any reference cited herein and thespecific teachings of this specification shall be resolved in favor ofthe latter. Likewise, any conflict between an art-understood definitionof a word or phrase and a definition of the word or phrase asspecifically taught in this specification shall be resolved in favor ofthe latter.

As used herein, whether in a transitional phrase or in the body of aclaim, the terms “comprise(s)” and “comprising” are to be interpreted ashaving an open-ended meaning. That is, the terms are to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a composition, the term“comprising” means that the composition includes at least the recitedfeatures or components, but may also include additional features orcomponents.

The terms “consists essentially of” or “consisting essentially of” havea partially closed meaning, that is, they do not permit inclusion ofsteps or features or components which would substantially change theessential characteristics of a process or composition; for example,steps or features or components which would significantly interfere withthe desired properties of the compositions described herein, i.e., theprocess or composition is limited to the specified steps or materialsand those which do not materially affect the basic and novelcharacteristics of the invention. The basic and novel features hereinare the provision of a combination of a compound of formula (I) with acompound of formula (II) which enhances the activity and/or duration ofaction of (I) for topical or other local application in the treatment ofinflammation.

The terms “consists of” and “consists” are closed terminology and allowonly for the inclusion of the recited steps or features or components.

As used herein, the singular forms “a,” “an” and “the” specifically alsoencompass the plural forms of the terms to which they refer, unless thecontent clearly dictates otherwise.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” or “approximately” is used herein to modify a numerical valueabove and below the stated value by a variance of 20%.

As used herein, the recitation of a numerical range for a variable isintended to convey that the invention may be practiced with the variableequal to any of the values within that range. Thus, for a variable whichis inherently discrete, the variable can be equal to any integer valueof the numerical range, including the end-points of the range.Similarly, for a variable which is inherently continuous, the variablecan be equal to any real value of the numerical range, including theend-points of the range. As an example, a variable which is described ashaving values between 0 and 2, can be 0, 1 or 2 for variables which areinherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other realvalue for variables which are inherently continuous.

In the specification and claims, the singular forms include pluralreferents unless the context clearly dictates otherwise. As used herein,unless specifically indicated otherwise, the word “or” is used in the“inclusive” sense of “and/or” and not the “exclusive” sense of“either/or.”

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001).

As used herein, “treating” means reducing, preventing, hindering orinhibiting the development of, controlling, alleviating and/or reversingthe symptoms in the individual to which a combination or composition ofthe invention has been administered, as compared to the symptoms of anindividual not being treated according to the invention. A practitionerwill appreciate that the combinations, compositions, dosage forms andmethods described herein are to be used in concomitance with continuousclinical evaluations by a skilled practitioner (physician orveterinarian) to determine subsequent therapy. Such evaluation will aidand inform in evaluating whether to increase, reduce or continue aparticular treatment dose, and/or to alter the mode of administration.

The methods of the present invention are intended for use with anysubject/patient that may experience the benefits of the methods of theinvention. Thus, in accordance with the invention, the terms “subjects”as well as “patients,” “individuals” and “warm-blooded animals” includehumans as well as non-human subjects, particularly domesticated animals,particularly dogs, cats, horses and cows, as well as other farm animals,zoo animals and/or endangered species.

While not wishing to be bound by any particular theory, it is believedthat the compounds of formula (II), while not themselves active asglucocorticoids, are able to enhance the glucocorticoid activity and/orduration of glucocorticoid action of the compounds of formulas (I) bycompeting with them in vivo for transcortin binding sites. The additionof the compound of formula (II) is believed to hinder efflux away fromthe site of local administration (which is also the site of action) ofthe active anti-inflammatory compound of formula (I) by competing withthe active compound for various in vivo systems which transport awayfrom the site. This is believed to thus contribute to an increase in theamount of free active compound available at the desired site ofaction/administration or to increase the time that the active compoundremains at the site, or both.

With respect to the various groups encompassed by the generic terms usedhere and throughout the specification, the definitions and explanationsgiven below are applicable.

R₁ is a straight or branched-chain alkyl radical having 1 to 7 carbonatoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, isobutyl and n-butyl.

Z is carbonyl or β-hydroxymethylene, preferably β-hydroxymethylene.

X is chloro or fluoro, preferably chloro.

R is H or straight or branched-chain alkyl having 1 to 4 carbon atoms; Ris preferably H, methyl or ethyl.

Z₁ is carbonyl or β-hydroxymethylene, preferably β-hydroxymethylene.

X₁ is —O— or —S—, preferably —O—.

R₅ is —OH, —OR₆, —OCOOR₆ or —OCOR₇ wherein R₆ is straight or branchedalkyl having 1 to 4 carbon atoms and R₇ is straight or branched alkylhaving 1 to 4 carbon atoms, fluoromethyl or chloromethyl; preferably, R₅is —OH.

In one embodiment of the invention, when R₅ in the compound of formula(II) is other than —OH, it may be selected to be identical to the17α-substituent in the compound of formula (I) with which it iscombined.

The dotted line in formulas (I) and (II) indicates that the A-ring canhave the Δ⁴ or Δ^(1,4) configuration. In the case of the compounds offormula (I), there is at present a preference for the Δ^(1,4)configuration. In the case of compounds of formula (I), it is mostpreferred that the structural variables, including the presence orabsence of a 1,2-double bond, correspond to those of loteprednoletabonate.

The compounds of formula (I) above are described in Bodor U.S Pat. No.4,996,335, incorporated by reference herein in its entirety and reliedupon. Specific compounds of formula (I) disclosed in that patent andrepresentative of compounds of formula (I) for use herein include thefollowing:

1. chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate,also known as loteprednol etabonate or LE;

2. chloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

3. chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate;

4. chloromethyl17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate;

5. chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

6. chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate;

7. chloromethyl11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

8. chloromethyl11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

9. fluoromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

10. chloromethyl11β-hydroxy-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate;and

11. chloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.

As especially preferred compound of formula (I) for use in the presentinvention is chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate,or loteprednol etabonate. Loteprednol etabonate and other preferredcompounds of formula (I) are those in which R₁ is methyl, ethyl,n-propyl, isopropyl, n-butyl or isobutyl, X is chloro, and Z is1-hydroxymethylene, most especially when the 1,2-linkage is unsaturated.These and other compounds of formula (I) can be prepared by methodsdescribed in the aforementioned '335 patent.

The compounds of formula (II) above have been variously described in thepatent and non-patent literature as chemical intermediates to and/orinactive putative metabolites of active anti-inflammatory steroids. By“inactive” is meant that the compounds of formula (II) do not havesignificant glucocorticoid binding activity and do not elicitanti-inflammatory, anti-allergic or vasoconstriction activity. Thepreparation of cortienic acid, i.e. 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid, from hydrocortisoneby treatment with sodium metaperiodate is detailed in Example 1 of BodorU.S. Pat. No. 4,996,335. Example 5B of that patent describes theanalogous preparation of17α-hydroxyandrost-4-en-3,11-dione-17β-carboxylic acid from cortisone;11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid fromprednisolone; and 17α-hydroxyandrosta-1,4-dien-3,11-dione-17β-carboxylic acid from prednisone. The process of preparing the17β-carboxylic acid from the corresponding 21-hydroxypregnenolones isgenerally described in column 10 of the '335 patent and in column 9 ofBodor U.S. Pat. No. 4,710,495. Example 10 of the '495 patent details asynthesis of 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylicacid, i.e. Δ¹-cortienic acid, from prednisolone. These patents describethe 17β-carboxylic acids of formula (II), i.e. the compounds in which—X₁R is —OH and R₅ is —OH, as chemical intermediates in the preparationof the compounds of formula (I) and other soft steroids. Thethiocarboxylic acids (—X₁R═—SH) can be prepared analogously. Preferred17β-carboxylic acids of formula (II) are cortienic acid and Δ¹-cortienicacid.

The carboxylic acid esters of formula (II), i.e. the compounds in which—X₁R is —O—(C₁-C₄ alkyl), can be prepared by combining 1 equivalent ofthe corresponding acid (—X₁R═—OH), i.e. cortienic acid or Δ¹-cortienicacid, with 1.5 equivalents of anhydrous potassium carbonate indimethylformamide (10 mL per gram of acid) or other suitable solvent,adding 3 equivalents of the selected C₁-C₄ alkyl iodide, such as methyliodide or ethyl iodide, stirring the mixture for 2 hours at roomtemperature, then diluting the reaction mixture with water toprecipitate the desired ester. The thiocarboxylic acid esters[—X₁R=—S—C₁-C₄ alkyl] can be prepared analogously starting from thethiocarboxylic acids. Preferred 17β-carboxylic acid esters of formula(II) are the methyl and ethyl esters of cortienic acid and the methyland ethyl esters of Δ¹-cortienic acid. These compounds are also referredto herein as cortienic acid methyl ester, cortienic acid ethyl ester,Δ¹-cortienic acid methyl ester and Δ¹-cortienic acid ethyl ester,respectively. Chemically, they can be named as methyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate; ethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate; methyl11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate; and ethyl11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate, respectively.Example 5 of Bodor U.S. Pat. No. 4,710,495, details an alternate processfor making these esters; it specifically describes methyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate, i.e. the17β-carboxylic acid methyl ester of cortienic acid, also referred toherein as cortienic acid methyl ester.

When —X₁R is —OH or —SH in formula (II), R₅ can be not only —OH asdiscussed above, but can alternatively be a carbonate (—OCOOR₆), ether(—OR₆) or ester (—OCOR₇) grouping. The preparation of the formula (II)17β-carboxylic acid 17α-carbonates/17β-thiocarboxylic acid17α-carbonates (X₁R═SH) is described in the aforementioned Bodor U.S.Pat. No. 4,996,335 and proceeds by reacting the corresponding acid orthio acid (R═H) of formula (II) with R₆OCOCl or R₆OCOBr (formed byreacting R₆OH with COCl₂ or COBr₂, wherein R₆ is defined as above),under anhydrous conditions in an appropriate inert organic solvent inthe presence of a suitable acid acceptor. Examples 2 (first paragraph),6A, 6B, 6C, 19 and 20 of the '335 patent describe preparation ofcompounds of this type. Representative specific compounds describedtherein which can be used in the present invention include:

-   1.    11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic    acid;-   2.    17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic    acid;-   3.    17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic    acid;-   4.    11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic    acid;-   5.    11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic    acid;-   6.    11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic    acid;-   7.    11β-hydroxy-17α-methoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylic    acid; and-   8.    17α-ethoxycarbonyloxy-11β-hydroxyandrost-1,4-dien-3-one-17β-carboxylic    acid.

Other specific compounds described in the '335 patent but not namedtherein which can be used in the present invention are identified inExample 6B of the patent as compound nos. 6B-1, 6B-2, and 6B-10 and canbe named as 17α-ethoxycarbonyloxyandrost-4-ene-3,11-dione-17β-carboxylicacid; 17α-methoxycarbonyloxyandrost-4-ene-3,11 -dione-17β-carboxylicacid; and17α-ethoxycarbonyloxyandrosta-1,4-diene-3,11-dione-17β-carboxylic acid,respectively.

The preparation of the formula (II) 17β-carboxylic acid17α-ethers/17β-thiocarboxylic acid 17α-ethers (X₁R═OH/SH; R₅═OR₆) isdescribed in the aforementioned Bodor U.S. Pat. No. 4,710,495.Typically, cortienic acid or Δ¹-cortienic acid or the corresponding X₁═Sacid is reacted with R₆l and KOH under anhydrous conditions, in an inertorganic solvent, preferably in the presence of a suitable acid acceptor,to afford the corresponding 17α-alkoxy 17β-carboxylic acid ester of theformula

which is thereafter converted to the desired 17β-carboxylic acid17α-ethers of the formula

by reaction with KOH, under anhydrous conditions, in an appropriateinert organic solvent. Representative specific compounds describedtherein which are suitable for use herein include11β-hydroxy-17α-methoxyandrost-4-en-3-one-17β-carboxylic acid (Examples3 and 23); 17α-ethoxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid(Examples 8 and 30);11β-hydroxy-17α-propoxyandrost-4-en-3-one-17β-carboxylic acid (Examples8 and 30); 17α-butoxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid(Examples 8 and 30);11β-hydroxy-17α-methoxyandrosta-1,4-dien-3-one-17β-carboxylic acid(Example 12); and11β-hydroxy-17α-propoxyandrosta-1,4-dien-3-one-17β-carboxylic acid(Example 12). Another compound of this type suitable for use hereinwhich can be prepared in analogous fashion is17α-ethoxy-11β-hydroxyandrost-1,4-dien-3-one-17β-carboxylic acid.

The formula (II) 17β-carboxylic acid 17α-esters and 17β-thiocarboxylicacid 17α-esters (X₁R═OH/SH; R₅═—OCOR₇) can be prepared by reacting thecorresponding acid or thio acid (R═H) of formula (II) with R₇ COCl orR₇COBr. Forexample,11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid(Δ¹-cortienic acid; 3.12 g, 9.0 mmol) is dissolved in a solution ofsodium bicarbonate (7.56 g, 90 mmol) in water (100 mL). Methylenechloride (100 mL) is added, followed by tetrabutylammoniumhydrogensulfate (1.0 g). The mixture is stirred vigorously and acetylchloride (17 mmol) in methylene chloride (10 mL) is added dropwise overa period of 5 minutes. Stirring is continued for approximately 5 hours,then the organic phase is separated and washed successively with 5%aqueous sodium bicarbonate solution, water, and saturated aqueous sodiumthiosulfate solution. The organic solution is dried over sodium sulfateand concentrated in vacuo. The resulting crude product,17α-acetoxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid, ispurified by chromatography. Substantial repetition of this procedureutilizing an equivalent quantity of propionyl chloride or butyrylchloride in place of the acetyl chloride affords11β-hydroxy-17α-propionyloxyandrosta-1,4-dien-3-one-17βcarboxylic acidand 17α-butyryloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylicacid, respectively. Similarly, repetition of this procedure, bututilizing an equivalent quantity of11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid together withacetyl chloride, propionyl chloride or butyryl chloride as the reactantsaffords, respectively,17α-acetoxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid,11β-hydroxy-17α-propionyloxyandrost-1,4-dien-3-one-17β-carboxylic acidand 17α-butyryloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate.

At the present time, compounds of formula (II) in which R₅ is —OH are ofparticular interest, especially those having the formula:

wherein R is H or C₁-C₄ alkyl and the dotted line indicates that the1,2-linkage is saturated or unsaturated, most especially when R is H,methyl or ethyl.

In the compositions and methods of the present invention, the enhancingagent of formula (II) and compound of formula (I) are generally used ina molar ratio of from about 5:1 to about 0.2:1 (preferably from about0.5:1 to about 1:1), that is, from about 0.2 to about 5 moles(preferably from about 0.5 to about 1 mole) of the formula (II) compoundfor each mole of compound of formula (I). In situations in which themolecular weight of the formula (II) compound is similar to that of theselected compound of formula (I), a weight/weight ratio of from about5:1 to about 0.2:1 (preferably 0.5:1 to 1:1, approximately) will closelyapproximate the about 5:1 to about 0.2:1 (preferably about 0.5:1 toabout 1:1) molar ratio and can be used instead for ease in formulatingpharmaceutical formulations. Indeed, even when the molecular weight ofthe compound of formula (I) is 10-20% greater than that of the formula(II) compound, the about 5:1 to about 0.2:1 (II):(I) (preferably about0.5:1 to about 1:1) weight ratio can be conveniently employed.

The present invention also provides a method for enhancing thehydrolytic stability of a compound of formula (I) by combining therewitha carboxylic acid of formula (II), that is, a compound of formula (II)wherein X₁R is OH and the other structural variables are defined asabove, in an amount sufficient to enhance the hydrolytic stability ofthe compound of formula (I). Of particular interest in this regard arethe compounds of formula (IIa) in which R is H, i.e. cortienic acid andΔ¹-cortienic acid. These acids of formula (II), especially the two acidsof formula (IIa) named above, when in solution produce an acidicenvironment which enhances the hydrolytic stability of the compound offormula (I), for example, of loteprednol etabonate. Generally speaking,the same amounts described herein as sufficient to enhance theanti-inflammatory activity and/or duration of action of the compound offormula (I) are also sufficient to enhance its hydrolytic stability.

The compounds of formulas (I) and (II) can be combined with suitablenon-toxic pharmaceutically acceptable carriers to provide pharmaceuticalcompositions for use in the treatment of topical or other localizedinflammation. Obviously, in view of their lack of systemic activity,compositions containing the compounds of formula (I) are not intendedfor treatment of conditions where systemic adrenocortical therapy isindicated, e.g., adrenocortical insufficiency. As examples ofinflammatory conditions which can be treated with pharmaceuticalcompositions containing the combination of a compound of formula (I) anda compound of formula (II) and one or more pharmaceutical carriers, thefollowing can be mentioned: dermatological disorders such as atopicdermatitis, acne, psoriasis or contact dermatitis; allergic states suchas bronchial asthma; ophthalmic and otic diseases involving acute andchronic allergic and inflammatory reactions (for example, ophthalmicinflammatory conditions such as blepharitis, conjunctivitis,episcleritis, scleritis, keratitis, anterior uveitis and sympatheticophthalmia, and ear inflammations of the outer and middle ear as well asinflammation of the inner ear, for example Meniere's Disease, injectedor instilled into the inner ear through the ear drum analogous to thecurrent use of dexamethasone); respiratory diseases; inflammations ofthe mouth, gums and/or throat, such as gingivitis or oral aphtha;inflammations of the nasal mucosa, for example, those caused byallergies; inflammations of the upper and lower intestines, such asCrohn's disease and ulcerative colitis; inflammations associated witharthritis; and anorectal inflammation, pruritus and pain associated withhemorrhoids, proctitis, cryptitis, fissures, postoperative pain andpruritus ani. Such compositions may also be applied locally as aprophylactic measure against the inflammation and tissue rejection whicharise in connection with transplants.

Obviously, the choice of carrier(s) and dosage forms will vary with theparticular condition for which the composition is to be administered.

Examples of various types of preparations for topical/localadministration include ointments, gels, lotions, creams, powders, drops(e.g., eye or ear or nose drops), sprays (e.g., for the nose or throat),suppositories, retention enemas, chewable or suckable tablets or pellets(e.g., for the treatment of aphthous ulcers) aerosols, tablets andcapsules.

Ointments and creams or gels may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agents and/or glycols. Such base may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a glycolic solvent such as propyleneglycol or 1,3-butanediol. Thickening agents which may be used accordingto the nature of the base include soft paraffin, aluminum stearate,cetostearyl alcohol, polyethylene glycols, woolfat, hydrogenated lanolinand beeswax and/or glyceryl monostearate and/or non-ionic emulsifyingagents.

The solubility of the steroids in the ointment or cream may be enhancedby incorporation of an aromatic alcohol such as benzyl alcohol,phenylethyl alcohol or phenoxyethyl alcohol.

Lotions may be formulated with an aqueous or oily base and will ingeneral also include one or more of the following, namely, emulsifyingagents, dispersing agents, suspending agents, thickening agents,solvents, coloring agents and perfumes.

Powders may be formed with the aid of any suitable powder base e.g.,talc, lactose or starch.

Drops may be formulated with an aqueous base also comprising one or moredispersing agents, suspending agents or solubilizing agents, etc.

Spray compositions may, for example, be formulated as aerosols with theuse of a suitable propellant, e.g., dichlorodifluoromethane ortrichlorofluoromethane.

Nebulized or powdered formulations may be prepared for oral inhalationin the treatment of asthma, as is well-known in the art.

Solutions and suspensions may be prepared for oral or rectaladministration for use in the treatment of inflammations of theintestines, for example, as described in more detail in the exampleshereinafter. Moreover, tablets, capsules and other oral dosage forms maybe used, for example, in the treatment of Crohn's disease, provided thatthey are formulated for delayed release (such as three hours afteradministration) to protect the compounds of formulas (I) and (II) fromgastric juice and to thus allow them to reach the target site, such asthe duodenum, before dissolving.

Parenteral/injectable formulations may be prepared for direct injectioninto the joints in the treatment of arthritis in accord with methodswell-known to those skilled in the art of parenteral formulations.

The amount of active ingredient and enhancer in the compositionsaccording to the invention will vary with the precise compounds used,the type of formulation prepared and the particular condition for whichthe composition is to be administered. The formulation will generallycontain from about 0.0001 to about 5.0% by weight of the compound offormula (I). Topical preparations will generally contain 0.0001 to 2.5%,preferably 0.01 to 0.5% of active compound, and will be administeredonce daily, or as needed. The identity and amount of active compoundwill determine the amount of formula (II) compound utilized therewith,in keeping with the desired molar or weight ratios discussed above.Also, generally speaking, the compounds of formulas (I) and (II) can beincorporated into topical and other local compositions formulatedsubstantially as are such presently available types of compositionscontaining known glucocorticosteroids, with the amount of compound offormula (I) varying according to its potency.

The compositions of the invention may be formulated to include otheractive compounds known to be useful in combination withanti-inflammatory steroids, for example, antifungal, antibacterial,antibiotic and local anaesthetic agents, for example, clotrimazole,clioquinol (iodochlorhydroxyquin), iodoquinol, polymyxin B sulfate,neomycin sulfate, tobramycin, sulfacetamide sodium, gentamicin,thonzonium bromide, colistin sulfate and pramoxine hydrochloride. Thesteroids of formulas (I) and (II) may be combined with more than one ofthese additional active agents when appropriate, for example, with acombination of polymyxin B sulfate and neomycin sulfate.

The anti-inflammatory activity of the compounds of formula (I) iswell-known from the aforementioned Bodor U.S. Pat. No. 4,996,335 and thescientific literature; as noted earlier, one of these compounds,loteprednol etabonate, is currently marketed in the United States forophthalmic administration as an anti-inflammatory agent. The marketed0.2% sterile ophthalmic suspension is indicated for the temporary reliefof signs and symptoms of seasonal allergic conjunctivitis while themarketed 0.5% sterile ophthalmic suspension is indicated for thetreatment of steroid-responsive inflammatory conditions of the palpebraland bulbar conjunctiva, cornea and anterior segment of the globe such asallergic conjunctivitis, acne rosacea, superficial punctate keratitis,herpes zoster keratitis, iritis, cyclitis, selected infectiveconjunctivitides, to reduce edema and inflammation. Other formulationsfor local administration for a variety of conditions are in clinicaltrials.

The combinations of the present invention have undergone humanvasoconstriction, or blanching, testing. Such testing gives a reliableindication of local anti-inflammatory/glucocorticoid activity. In thepresent case, it has been used to show that representative enhancingagents of formula (II) are inactive alone, that a representativecompound of formula (I) is active alone, and that administering acompound of formula (II) with a compound of formula (I) enhances theanti-inflammatory activity or duration of action or both of therepresentative formula (I) compound.

Human Vasoconstriction Testing

Test compounds at varying mM concentrations as noted below weredissolved in ethanol/propylene glycol (9/1) solution, and 20 μL of themixtures were applied to filter paper discs, 0.7 cm in diameter. Afterethanol evaporation, each disc was attached to waterproof adhesive tape,then applied to the forearm of a human volunteer and left in place for 4hours. Groups of 8 forearms were tested at each concentration. Theintensity of vasoconstriction was judged at 2, 4, 6, 8, 10, 12, 18, 24and 36 hours after removal of the discs.

The grading scale for the vasoconstriction activity was as follows: 0,normal skin; 1, slight pallor of indistinct outline; 2, pallor with atleast two corners outlined; 3, even pallor with a clear outline of theapplication sites; 4, very intense pallor. The scores were totaled ateach concentration at each time after removal to give a total score ateach time interval and an overall total for each concentration. Thehigher the total score, the greater the blanching or anti-inflammatoryeffect.

Tested in this manner were loteprednol etabonate, Δ¹-cortienic acid, themethyl ester of Δ¹-cortienic acid, a combination of loteprednoletabonate plus Δ¹-cortienic acid, and a combination of loteprednoletabonate plus the methyl ester of Δ¹-cortienic acid. The structures ofthe test compounds are shown below:

The results were as follows, where AUC was estimated as the sum of theindividual scores through 36 hours.

Concentration mM % by weight AUC Loteprednol Etabonate 0.1 0.0047%  90.5 0.023%  39 1   0.047%  90 5   0.23% 117 10   0.47% 122 Δ¹-CortienicAcid 0.5 0.017%  0 2.5 0.09% 0 5   0.17% 0 25   0.87% 0 50   1.73% 0Δ¹-Cortienic Acid Methyl Ester 0.5 0.018%  0 2.5 0.09% 0 5   0.18% 025   0.90% 0 50   1.80% 0 Loteprednol Etabonate + Δ¹-Cortienic AcidConcentration (mM) LE Δ¹-CA AUC 0.1 0.5 36 0.5 2.5 78 1   5 112 5   25127 10   50 128 Loteprednol Etabonate + Δ¹-Cortienic Acid Methyl EsterConcentration (mM) LE Δ¹-MeCA AUC 0.5 0.5 40 2.5 2.5 91 5   5 117 25  25 128 50   50 132

The results indicate that neither Δ¹-cortienic acid nor Δ¹-cortienicacid methyl ester had any vasoconstriction activity when tested alone.Loteprednol etabonate alone exhibited significant activity, as would beexpected. Surprisingly, Δ¹-cortienic acid and Δ¹-cortienic acid methylester each significantly enhanced the vasoconstrictor activity ofloteprednol etabonate, especially at the lower concentrations tested. A1:5 molar ratio of loteprednol etabonate: Δ¹-cortienic acid or itsmethyl ester was used throughout.

It was also found that the activity of loteprednol etabonate alone beganto decrease between 12 and 18 hours after removal of the disc, adecrease which was even more apparent at the 24 hour interval.Δ¹-Cortienic acid and Δ¹-cortienic methyl ester were each able to extendthe time period during which loteprednol etabonate displayed significantactivity, to 24 hours or more at some tested concentrations.

This testing clearly showed the synergistic effect which Δ¹-cortienicacid and its methyl ester each exert on the anti-inflammatory action ofloteprednol etabonate as well as on its duration of action.

Further Human Vasoconstriction Testing Objective

The objective of this study is to evaluate the effect of Δ¹-cortienicacid (Δ¹-CA) and the methyl ester of Δ¹-cortienic acid (Δ¹-MeCA) on thevasoconstriction effect of loteprednol etabonate (LE) and betamethasone17-valerate (BEM-17V). The structures of LE, Δ¹-CA and Δ¹-MeCA are givenabove. BEM-17V has the structure:

and was used for comparison purposes.

Methodology

LE (0.2 mM), BEM-17V (0.2 mM), Δ¹-CA (0-1 mM) and Δ¹-MeCA (0-1 mM)solutions were made by dissolving the compounds in a vehicle containingabsolute ethanol and propylene glycol (9:1). The resultant LE andBEM-17V solutions were then mixed (1:1) with vehicle only, or with theΔ¹-CA or Δ¹-MeCA solutions, so that LE solutions (0.1 mM) and BEM-17Vsolutions (0.1 mM) containing various concentrations of Δ¹-CA (0 to 0.5mM) or Δ¹-MeCA (0 to 0.5 mM) were obtained. The resultant mixtures (20μl) were loaded onto circular patches (6.5 mm diameter) that wereattached to a water impervious adhesive film (3M). After the evaporationof ethanol, the patches and film were applied to the forearms of humanvolunteers for 4 hours. Subsequently, the vasoconstriction reaction wasjudged by the appearance of pallor at various time intervals after theremoval of the patches (2, 4, 6, 8, 10, 12, 18, 20 and 24 hours afterremoval and also 36 hours after removal in the case of BEM-VAL). Thegrading scale was as follows: 0, normal skin; 1, slight pallor; 2,pallor with at least two corners outlined; 3, even pallor with a clearoutline of the application sites; 4, very intense pallor. Due to theresponse variations among the volunteers, control tests (0 mM Δ¹-CA andΔ¹-MeCA) were performed on each tested arm at the same time, and thetotal scores of the tests were taken at each time period and compared.As before, an overall total for each concentration was then obtained.The results were as follows, where AUC was estimated as the sum of theindividual scores through 24 hours.

Results And Discussion

Loteprednol Etabonate + Δ¹-Cortienic Acid Concentration (mM) LE Δ¹-CAAUC 0.1 0 99 0.1 0.1 122 0.1 0.2 121 0.1 0.3 123 0.1 0.4 125 0.1 0.5 116Loteprednol Etabonate + Δ¹-Cortienic Acid Methyl Ester Concentration(mM) LE Δ¹-MeCA AUC 0.1 0 114 0.1 0.1 121 0.1 0.2 123 0.1 0.3 127 0.10.4 126 0.1 0.5 122 Betamethasone Valerate + Δ¹-Cortienic AcidConcentration (mM) BEM-17V Δ¹-CA AUC 0.1 0 107 0.1 0.1 107 0.1 0.2 1070.1 0.3 107 0.1 0.4 107 0.1 0.5 107 Betamethasone Valerate +Δ¹-Cortienic Acid Methyl Ester Concentration (mM) BEM-17V Δ¹-MeCA AUC0.1 0 112 0.1 0.1 112 0.1 0.2 112 0.1 0.3 112 0.1 0.4 112 0.1 0.5 112

Human vasoconstriction tests have been used to evaluate the percutaneousabsorption, activity and bioavailability of glucocorticoids. Thevasoconstriction activity of LE, and the effect of Δ¹-CA and Δ¹-MeCA onthe activity of LE have been studied and reported hereinabove. In thepresent study, the effects of Δ¹-CA and Δ¹-MeCA on the activities of LEand BEM-17V were compared at varying molar ratios of drug to Δ¹-CA andΔ¹-MeCA. The results shown in the first two tables indicate that, as inthe previous studies, Δ¹-CA and Δ¹-MeCA both increased thevasoconstriction activity of LE. Ratios of 1:1 of LE: Δ¹-CA and Δ¹-MeCAgave very similar results to those obtained for 1:2, 1:3, 1:4 and 1:5ratios, with 1:5 ratios showing slightly less activity. All of theseratios showed synergistic results. In other words, molar ratios of (II)to (I) of from 5:1 to 1:1 showed synergism. Ratios of about 1:1 appearmost useful; increasing the ratio of (II) to (I) to 2:1 or even 5:1 doesnot give better results. In the case of BEM-17V, no activity-increasingeffect of Δ¹-CA and Δ¹-MeCA was observed, as shown in the third andfourth tables above.

The following Examples illustrate numerous formulations suitable foradministering the combinations of a compound of formula (I) and acompound of formula (II) to treat various kinds of local inflammatoryconditions. These formulations are merely illustrative and notlimitative of the remainder of the specification and claims in any waywhatsoever.

In these Examples, percentages are by weight unless otherwise noted.

EXAMPLE 1

A nasal suspension is prepared having the following composition:

NASAL SUSPENSION Loteprednol etabonate (LE) 0.5 to 1.0 g Δ¹-Cortienicacid 2.5 to 5.0 g (in 5:1 ratio to LE) Concentrated glycerin 2.6 gPolysorbate 80 0.2 g Microcrystalline cellulose 2.0 to 3.0 g carmellosesodium Citric acid q.s. Benzalkonium chloride 0.005 g Purified waterq.s. 100 g (pH 5.5)

The suspension can be prepared in accord with the procedure described inDoi U.S. Pat. No. 6,368,616 B1 of Apr. 9, 2002, incorporated byreference herein in its entirety and relied upon, except for theaddition of Δ¹-cortienic acid, which can occur at the same time as theaddition of loteprednol etabonate.

Alternatively, from 0.5 to 1.0 g of Δ¹-cortienic acid may be usedinstead of the 2.5 to 5.0 g amount listed above.

EXAMPLE 2

A nasal suspension is prepared having the following composition:

NASAL SUSPENSION Loteprednol etabonate 0.5 g Δ¹-Cortienic acid methylester 0.25 to 2.5 g Propylene glycol 2.0 g Polyoxyethylene hydrogenatedcastor oil 60 0.2 g Microcrystalline cellulose carmellose sodium 3.0 gPhosphoric acid q.s. Benzethonium chloride 0.005 g Purified water q.s.100 g (pH 5.5)

The suspension can be prepared in accord with the procedure of theaforementioned '616 patent, except for the addition of Δ¹-cortienic acidmethyl ester, which can occur at the same time as the addition ofloteprednol etabonate.

The foregoing nasal formulations can be modified as described in the'616 patent.

The following formulations can be prepared using routine productionprocedures for formulations of these types.

EXAMPLE 3

An eye drop suspension is prepared having the following composition:

EYE DROP SUSPENSION Loteprednol etabonate 0.5 g Δ¹-Cortienic acid methylester 0.25 to 2.0 g ε-Aminocaproic acid 0.1 g Tyloxapol 0.3 gPolyvinylpyrrolidone (intrinsic viscosity = 30) 0.6 g Sodium edetate0.01 g Benzalkonium chloride (10 w/v %) 0.05 mL Hydrochloric acid q.s.Sterilized pure water q.s. 100 mL pH 5.53

0.05 to 0.1 mL of this suspension can be distilled into the eye 3 to 10times daily.

This suspension formulation can be modified as described in Inada et alU.S. Pat. No. 5,916,550, of Jun. 29, 1999, incorporated by referenceherein in its entirety and relied upon, except for the addition ofΔ¹-cortienic acid methyl ester at the time of loteprednol etabonateincorporation, to provide other aqueous suspensions for use in the eyeor nose which do not undergo pH depression even after prolonged storage.

EXAMPLE 4

An ointment is prepared having the following composition:

OINTMENT Compound of formula (I) e.g. 0.10% w/w loteprednol etabonateCompound of formula (II), e.g. 0.10 to 0.40% w/w Δ¹-cortienic acidmethyl ester Liquid paraffin 10.0% ww White soft paraffin 89.5% w/w

EXAMPLE 5

An aphthous ulcer pellet is prepared having the following composition:

APHTHOUS ULCER PELLET Compound of formula (I), e.g. loteprednoletabonate 0.20 mg Compound of formula (II), e.g. Δ¹-cortienic acid 0.20to 0.80 mg Lactose 69.0 mg Acacia 3.00 mg Magnesium stearate 0.75 mg

EXAMPLE 6

A retention enema is prepared having the following composition:

RETENTION ENEMA Compound of formula (I), e.g. 0.01% w/v loteprednoletabonate Compound of formula (II), e.g. 0.01% to 0.03% w/v Δ¹-cortienicacid methyl ester Tween 80 0.05% w/v Ethanol 0.015% w/v Propylparaben0.02% w/v Methylparaben 0.08% w/v Distilled water q.s. 100 volumes

EXAMPLE 7

Eye drops are prepared having the following composition:

EYE DROPS Compound of formula (I), e.g. 0.2% w/v loteprednol etabonateCompound of formula (II), 0.20 to 0.80% w/v e.g. Δ¹-cortienic acid Tween80 2.5% w/v Ethanol 0.75% w/v Benzalkonium chloride 0.02% w/v Phenylethanol 0.25% w/v Sodium chloride 0.60% w/v Water for injection q.s. 100volumes

EXAMPLE 8

A dermal ointment is prepared having the following composition:

DERMAL OINTMENT Compound of formula (I), e.g. loteprednol etabonate 0.2%w/w Compound of formula (II), e.g. Δ¹-cortienic acid 0.1 to 1.0% w/wLiquid Paraffin 10.0% w/w White soft paraffin 88.8% w/w

EXAMPLE 9

An aphthous ulcer pellet is prepared having the following composition:

APHTHOUS ULCER PELLET Compound of formula (I), e.g. loteprednoletabonate 0.15 mg Compound of formula (II), e.g. Δ¹-cortienic acid 0.10to 0.45 mg methyl ester Lactose 60.25 mg Acacia 3.0 mg Magnesium sterate0.75 mg

EXAMPLE 10

A retention enema is prepared having the following composition:

RETENTION ENEMA Compound of formula (I), e.g. 0.005% w/v loteprednoletabonate Compound of formula (II), e.g. 0.003 to 0.025% w/vΔ¹-cortienic acid Tween 80 0.05% w/v Ethanol 0.015% w/v Propylparaben0.02% w/v Methylparaben 0.08% w/v Distilled water q.s. 100 volumes

EXAMPLE 11

Eye drops are prepared having the following composition:

EYE DROPS Compound of formula (I), e.g. 0.1% w/v loteprednol etabonateCompound of formula (II), 0.1 to 0.5% w/v e.g. Δ¹-cortienic acid methylester Tween 80 2.5% w/v Ethanol 0.75% w/v Benzalkonium chloride 0.02%w/v Phenyl ethanol 0.25% w/v Sodium chloride 0.60% w/v Water forinjection q.s. 100 volumes

EXAMPLE 12

Eye drops are prepared having the following composition:

EYE DROPS Compound of formula (I), e.g. 0.5% w/v loteprednol etabonateCompound of formula (II), e.g. 0.25 to 1.5% w/v Δ¹-cortienic acidPovidone 0.6% w/v Benzalkonium chloride 0.02% w/v Sodium edetate U.S.P.0.10% w/v Glycerin U.S.P. 2.5% w/v Tyloxapol U.S.P. 3.0% w/v Sodiumchloride 0.3% w/v Sodium γ-aminobutyrate 1.0% w/v Sterile distilledwater q.s. 100 volumes

The ingredients listed above are combined, then the pH is checked and,if necessary, adjusted to 5.0-5.5 by basifying with sodium hydroxide oracidifying with hydrochloric acid.

Yet other compositions of the invention can be conveniently formulatedusing known techniques.

Thus, for example, an inhalation formulation suitable for use in thetreatment of asthma can be prepared as a metered-dose aerosol unitcontaining a representative compound of formula (I) such as loteprednoletabonate and a representative compound of formula (II) such ascortienic acid, cortienic acid methyl ester, Δ¹-cortienic acid orΔ¹-cortienic methyl ester, according to procedures well-known to thoseskilled in the art of pharmaceutical formulations. Such an aerosol unitmay contain a microcrystalline suspension of loteprednol etabonate andone of the aforementioned compounds of formula (II) in a I:(II) weightratio of from 0.5:1 to 1:3 in suitable propellants (e.g.trichlorofluoromethane and dichlorodifluoromethane anddichlorotetrafluoroethane), with oleic acid, sorbitan trioleate or othersuitable dispersing agent. Each unit typically contains 1-10 milligramsof the aforesaid loteprednol etabonate, approximately 5-50 micrograms ofwhich are released at each actuation.

Another example of a pharmaceutical composition according to theinvention is a foam suitable for treatment of a wide variety ofinflammatory anorectal disorders, to be applied anally or perianally,comprising 0.1% or 0.5% of a compound of formula (I) such as loteprednoletabonate and 0.2% or 1.0%, respectively, of Δ¹-cortienic acid or itsmethyl ester, and 1% of a local anaesthetic such as pramoxinehydrochloride, in a mucoadhesive foam base of propylene glycol,ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ether, cetylalcohol, methyl paraben, propyl paraben, triethanolamine, and water,with inert propellants. Alternatively, 0.2% or 1.0% of Δ¹-cortienic acidor its methyl ester may be employed (in a 1:1 ratio of (I):(II)).

Yet another pharmaceutical formulation according to the invention is asolution or suspension suitable for use as a retention enema, a singledose of which typically contains 40-80 milligrams of a compound offormula (I) such as loteprednol etabonate and from ½ to 5 times thatamount of a compound of formula (II), preferably Δ¹-cortienic acid orΔ¹-cortienic acid methyl ester, together with sodium chloride,polysorbate 80 and 1 to 6 ounces of water (the water being added shortlybefore use). The suspension can be administered as a retention enema orby continuous drip several times weekly in the treatment of ulcerativecolitis.

Another exemplary formulation is a sterile, multiple dose antibiotic andsteroid combination suspension for topical ophthalmic use. Each mL ofsuspension contains: as active ingredients, tobramycin 0.3% (3 mg) andloteprednol etabonate 0.5% (5 mg); as synergist, Δ¹-cortienic acid 0.25to 1.0% (2.5 to 10 mg); as preservative, benzalkonium chloride 0.01%;and as inactives tyloxapol, edetate disodium, sodium chloride,hydroxyethyl cellulose, sodium sulfate, sulfuric acid and/or sodiumhydroxide (to adjust pH) and purified water.

Another example is a sterile, multiple dose antibiotic and steroidcombination ointment for topical ophthalmic use. Each gram of ointmentcontains: as active ingredients, tobramycin 0.3% (3 mg) and loteprednoletabonate 0.2% (2 mg); as synergist, Δ¹-cortienic acid methyl ester 0.2%to 1.0% (2 to 10 mg); as preservative, chlorobutanol 0.5%; and asinactives, mineral oil and white petrolatum.

Yet another exemplary formulation is a ophthalmicanti-infective/anti-inflammatory sterile suspension containing: asactive ingredients, sulfacetamide sodium 10% and loteprednol etabonate(microfine suspension) 0.5%; as synergist, Δ¹-cortienic acid methylester 0.5 to 1.5%; as preservative, benzalkonium chloride (0.004%); asinactives, polyvinyl alcohol 1.4%, polysorbate 80, edetate disodium,dibasic sodium phosphate, monobasic potassium phosphate, sodiumthiosulfate, hydrochloric acid and/or sodium hydroxide to adjust the pH,and purified water. A similar composition may be formulated for oticadministration.

Another ophthalmic ointment containing an antibacterial and acorticosteroid is exemplified by a sterile ointment containing: asactives, sulfacetamide sodium 10% and loteprednol etabonate, 0.2%; assynergist, Δ¹-cortienic acid, 0.1% to 1.0%; as preservative,phenylmercuric acetate (0.0008%); and as inactives, mineral oil, whitepetrolatum, and petrolatum and lanolin alcohol.

Another example of a sterile ophthalmic formulation is a topicalanti-inflammatory/anti-infective suspension containing, as activeingredients, loteprednol etabonate (microfine suspension) 0.5%, neomycinsulfate equivalent to 0.35% neomycin base, polymyxin B sulfate 10,000units/mL; as synergist, Δ¹-cortienic acid methyl ester, 0.25 to 1.0%; aspreservative, thimerosal 0.001%; and as inactive ingredients, polyvinylalcohol 1.4%, polysorbate 80, propylene glycol, sodium acetate andpurified water.

Yet another illustrative sterile ophthalmic suspension which is atopical anti-inflammatory/anti-infective combination product contains:as active ingredients, gentamicin sulfate equivalent to 0.3% gentamicinbase and loteprednol etabonate (microfine suspension) 0.5%; assynergist, Δ¹-cortienic acid or its methyl ester, 0.5 to 1.0%; aspreservative, benzalkonium chloride 0.005%; as inactive ingredients,polyvinyl alcohol 1.4%, edetate disodium, hydroxypropyl methylcellulose,polysorbate 80, sodium citrate dihydrate, sodium chloride and purifiedwater. The composition may contain sodium hydroxide and/or hydrochloricacid to adjust the pH to be in the range of 5.5 to 6.6.

Another sterile ophthalmic suspension formulation contains, per mL: asactive, loteprednol etabonate 2 mg (0.2%); as synergist, Δ¹-cortienicacid methyl ester 0.5 to 5 mg (0.05 to 0.5%); as preservative,benzalkonium chloride 0.01%; as inactives, edetate disodium, glycerin,povidone, purified water and tyloxapol. Hydrochloric acid and/or sodiumhydroxide may be added to adjust the pH to 5.3 to 5.6.

Yet another sterile ophthalmic suspension formulation contains, per mL:as active ingredient, loteprednol etabonate 5 mg (0.5%); as synergist,Δ¹-cortienic acid 5 to 15 mg (0.5 to 1.5%); as preservative,benzalkonium chloride 0.01%; as inactive ingredients, edetate disodium,glycerine, povidone, purified water and tyloxapol. Hydrochloric acidand/or sodium hydroxide may be added to adjust the pH to 5.3 to 5.6.

For dermatological use, in the treatment of fungal infections withassociated inflammation, a cream or lotion combining clotrimazole, asynthetic antifungal agent, a compound of formula (I) and a compound offormula (II) may be formulated. A suitable cream or lotion contains, ineach gram of cream or lotion: 10 mg of clotrimazole, 0.5 mg ofloteprednol etabonate and 0.25 to 2.0 mg of Δ¹-cortienic acid, in ahydrophilic cream or lotion base consisting of purified water, mineraloil, white petrolatum, cetearyl alcohol 70/30, ceteareth-30, propyleneglycol, sodium phosphate monobasic monohydrate and phosphoric acid, withbenzyl alcohol as a preservative. If necessary, the lotion may containsodium hydroxide.

Capsules or tablets suitable for oral administration in the treatment ofCrohn's disease may be formulated to protect the compounds of formulas(I) and (II) from gastric juice and to dissolve when they reach a higherpH in the duodenum. In one formulation of this type, each capsulecontains 5-20 mg of micronized loteprednol etabonate, 5-80 mg ofmicronized Δ¹-cortienic acid methyl ester (in a weight ratio of 1:1 to4:1 of Δ¹-cortienic acid methyl ester to loteprednol etabonate), withethyl cellulose, acetyl tributyl citrate, methacrylic acid copolymertype C, triethyl citrate, antifoam M, polysorbate 80, talc and sugarspheres, in a shell composed of gelatin, iron oxide and titanium oxide.The granules in the formulation are coated to prevent dissolution ingastric juice but dissolve at pH>5.5, normally when the granules reachthe duodenum. After that, a matrix of ethyl cellulose with the steroidsreleases them in a time-dependent manner in the intestinal lumen.

For the treatment of asthma, a sterile suspension for oral inhalationvia a compressed air-driven jet nebulizer may be formulated. Thesuspension contains, as the active ingredient, micronized loteprednoletabonate; as the enhancing agent, micronized Δ¹-cortienic acid orΔ¹-cortienic acid methyl ester (in a 0.5:1 to 2:1 weight ratio toloteprednol etabonate); and as inactives, disodium edetate, sodiumchloride, sodium citrate, citric acid, polysorbate 80, and water forinjection. Single dose ampules contain 0.5, 1.0, 1.5 and 2.0 mg ofloteprednol etabonate.

An alternate preparation for the treatment of asthma is aninhalation-driven multidose dry powder inhaler containing onlymicronized loteprednol etabonate and micronized Δ¹-cortienic acid. Eachactuation is designed to provide 400 mcg of loteprednol etabonate and500 mcg of Δ¹-cortienic acid and to act directly on the respiratorytract.

For the treatment and management of nasal symptoms of seasonal orperennial allergic rhinitis, a nasal spray or gel may be used. One suchnasal formulation is a metered-dose, manual pump spray containing amicronized suspension of loteprednol etabonate and Δ¹-cortienic acidmethyl ester in an aqueous medium. The medium also containsmicrocrystalline cellulose and carboxymethyl cellulose sodium, anhydrousdextrose, polysorbate 80, disodium edetate, potassium sorbate andpurified water, with hydrochloric acid added to adjust the pH to about4.5. The formulation is designed to deliver 50 or 100 mcg of loteprednoletabonate and 50 to 150 or 100 to 300 mcg, respectively, of Δ¹-cortienicacid methyl ester per spray.

To treat the pruritic and inflammatory manifestations ofanti-inflammatory steroid-responsive dermatoses, especially localizedlesions which are dry and scaly, a tape containing the active ingredientand enhancer may be used as both a vehicle and an occlusive dressing.One such product is a moisture-impervious plastic surgical tapecontaining loteprednol etabonate and Δ¹-cortienic acid. Each squarecentimeter of tape contains 10 pg of loteprednol etabonate and 10 to 40pg of Δ¹-cortienic acid evenly distributed in the adhesive layer. Thetape is made of polyethylene film, while the adhesive is a syntheticcopolymer of acrylate ester and acrylic acid.

For the treatment of ulcerative colitis, a rectal suspension in adisposable single-dose enema may be formulated for readyself-administration. A typical disposable single dose unit for rectaladministration contains 60 mL of suspension containing: 10-100 mg ofloteprednol etabonate and 10-100 or 30-300 mg of Δ¹-cortienic acid (in a1:1 or 3:1 weight ratio to loteprednol etabonate) in an aqueous solutioncontaining carbomer 934P, polysorbate 80, purified water, sodiumhydroxide and methyl paraben.

For the treatment of superficial bacterial infections of the externalauditory canal and treatment of infections of mastoidectomy andfenestration cavities accompanied by inflammation, an otic suspensionmay be used. One such suspension contains colistin sulfate and neomycinsulfate as antibiotics, the selected steroids of formulas (I) and (II)and thonzonium bromide, a surface-active agent; for example, asuspension which contains, per mL: colistin base activity, 3 mg (as thesulfate); neomycin base activity, 3.3 mg (as the sulfate); loteprednoletabonate, 10 mg (1%); Δ¹-cortienic acid, 10 to 40 mg (1 to 4%),thonzonium bromide, 0.5 mg (0.5%), polysorbate 80, acetic acid andsodium acetate in a buffered aqueous vehicle. Thimerosal (0.002%) isadded as a preservative. The suspension is buffered at pH 5.

A foam may be formulated for use in the treatment of inflammatory andpruritic manifestations of corticosteroid-responsive dermatoses of theanal region. An exemplary foam contains 1% loteprednol etabonate, 0.5 to3% Δ¹-cortienic acid methyl ester, and 1% pramoxine hydrochloride (alocal anaesthetic) in a hydrophilic base containing cetyl alcohol,emulsifying wax, methyl paraben, polyoxyethylene-10 stearyl ether,propylene glycol, propyl paraben, purified water, trolamine, isobuteneand propane.

For intramuscular, intrasynovial, soft tissue or intralesional injectionfor various conditions, especially for intrasynovial or soft tissueinjection as therapy in synovitis of osteoarthritis, rheumatoidarthritis, acute and subacute bursitis, acute gouty arthritis,epicondylitis, acute nonspecific tenosynovitis and post-traumaticosteoarthritis, a sterile aqueous suspension may be formulated. Each mLof suspension contains 20, 40 or 80 mg/mL of loteprednol etabonate; and20, 40 or 80 or 40, 80 or 160 mg/mL, respectively, of Δ¹-cortienic acidmethyl ester; together with polyethylene glycol 3350, polysorbate 80,monobasic sodium phosphate, dibasic sodium phospate USP, benzyl alcohol(as preservative), sodium chloride (to adjust tonicity) and whennecessary to adjust pH to within 3.5 to 7.0, sodium hydroxide and/orhydrochloric acid.

For use in the treatment of inflamed hemorrhoids, post irradiationproctitis, as an adjunct in the treatment of chronic ulcerative colitis,cryptitis, other inflammatory conditions of the anorectum and pruritusani, suppositories may be formulated. One such suppository contains10-25 mg loteprednol etabonate and 10-25 or 40-100 mg Δ¹-cortienic acid(in a 1:1 or 4:1 weight ratio to the loteprednol etabonate) in ahydrogenated cocoglyceride base.

For relief of the inflammatory and pruritic manifestations ofcorticosteroid-responsive dermatoses of the anal region, a rectal creammay be used. An illustrative rectal cream contains 1% loteprednoletabonate, 1% Δ¹-cortienic acid methyl ester and 1% pramoxinehydrochloride (a topical anaesthetic) in a washable, nongreasy basecontaining stearic acid, cetyl alcohol, aquaphor, isopropyl palmitate,polyoxyl 40 stearate, propylene glycol, potassium sorbate 0.1%, sorbicacid 0.1%, triethanolamine, lauryl sulfate and water.

For various dermal conditions having both an inflammatory/pruriticcomponent and a fungal/bacterial component, a topical cream compositionmay be formulated to contain a compound of formula (I), a compound offormula (II) and iodoquinol (as an antifungal and antibacterial agent).An illustrative cream contains, per gram, 10 mg of loteprednoletabonate, 5 to 20 mg of Δ¹-cortienic acid and 10 mg of iodoquinol in agreaseless base of purified water, propylene glycol, glycerylmonostearate SE, cholesterol and related sterols, isopropyl myristate,polysorbate 60, cetyl alcohol, sorbitan monostearate, polyoxyl 40stearate, sorbic acid and polysorbate 20.

Another topical preparation for dermatological use in treatingconditions with an inflammatory/pruritic component and afungal/bacterial component may be formulated to contain a compound offormula (I), a compound of formula (II) and iodochlorhydroxyquin (alsoknown as clioquinol), which has antifungal and antibacterial properties.These ingredients are, for example, formulated as a cream, ointment orlotion containing 3% iodochlorhydroxyquin, 0.5% or 1.0% loteprednoletabonate and 0.5-2.0% or 1.0-4.0%, respectively, Δ¹-cortienic acidmethyl ester.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A method for enhancing the anti-inflammatory activity or duration ofaction, or both, of a compound having the formula:

wherein: R₁ is C₁-C₇ alkyl; Z is carbonyl or β-hydroxymethylene; X is Clor F; and the dotted line in ring A indicates that the 1,2-linkage issaturated or unsaturated; following topical or other localadministration of said compound to a warm-blooded animal in need oftreatment to alleviate a topical or other localized inflammatoryresponse, said method comprising topically or otherwise locallyco-administering said compound to said animal with a synergisticallyeffective amount of a compound having the formula:

wherein: R is H or C₁-C₄ alkyl; Z₁ is carbonyl or β-hydroxymethylene; X₁is —O— or —S—; R₅ is —OH, —OR₆, —OCOOR₆ or —OCOR₇ wherein R₆ is C₁-C₄alkyl and R₇ is C₁-C₄ alkyl, fluoromethyl or chloromethyl; and thedotted line is defined as above; with the proviso that when R is C₁-C₄alkyl, then R₅ is —OH; the amount of compound of formula (II) beingsufficient to enhance the anti-inflammatory activity or duration ofaction, or both, of said compound of formula (I); with the proviso that[3H]-triamcinolone acetonide is excluded.
 2. A method according to claim1, wherein the compound of formula (I) is: (a) chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate;(b) chloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;(c) chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate; (d)chloromethyl17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate; (e)chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;(f) chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate;(g)chloromethyl-11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;(h) chloromethyl11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;(i) fluoromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;(j) chloromethyl11β-hydroxy-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate;or (k) chloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.3. A method according to claim 1, wherein the compound of formula (I) isloteprednol etabonate.
 4. A method according to claim 1, wherein thecompound of formula (II) is: (a)11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid; (b)11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid; (c) methyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate; (d) ethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate; (e) methyl11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate; or (f) ethyl11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.
 5. A methodaccording to claim 1, wherein the molar ratio of compound of formula(II) to compound of formula (I) is from about 5:1 to about 0.5:1.
 6. Amethod for enhancing the anti-inflammatory activity or duration ofaction, or both, of loteprednol etabonate following topical or otherlocal administration thereof to a warm blooded animal in need oftreatment to alleviate a topical or other localized inflammatoryresponse, said method comprising topically or otherwise locallyco-administering loteprednol etabonate to said animal with asynergistically effective amount of a compound having the formula:

wherein R is H or C₁-C₄ alkyl and the dotted line in ring A indicatesthat the 1,2-linkage is saturated or unsaturated, the amount of compoundof formula (IIa) being sufficient to enhance the anti-inflammatoryactivity or duration of action, or both, of loteprednol etabonate, withthe proviso that [3H]-triamcinolone acetonide is excluded.
 7. A methodaccording to claim 6, wherein the compound of formula (IIa) is11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid or methyl11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.
 8. A methodaccording to claim 7, wherein the molar ratio of compound of formula(IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.
 9. Amethod for alleviating inflammation in or on a warm-blooded animalexhibiting a topical or other localized inflammatory response, whichcomprises topically or otherwise locally administering to said animal ananti-inflammatory effective amount of a combination comprising: (a) acompound having the formula:

wherein: R₁ is C₁-C₇ alkyl; Z is carbonyl or β-hydroxymethylene; X is Clor F; and the dotted line in ring A indicates that the 1,2-linkage issaturated or unsaturated; and (b) a compound having the formula:

wherein: R is H or C₁-C₄ alkyl; Z₁ is carbonyl or β-hydroxymethylene; X₁is —O— or —S—; R₅ is —OH, —OR₆, —OCOOR₆ or —OCOR₇ wherein R₆ is C₁-C₄alkyl and R₇ is C₁-C₄ alkyl, fluoromethyl or chloromethyl; and thedotted line is defined as above; with the proviso that when R is C₁-C₄alkyl, then R₅ is —OH; in a combined synergistic anti-inflammatoryeffective amount; the amount of compound of formula (II) beingsufficient to enhance the anti-inflammatory activity or duration ofaction, or both, of said compound of formula (I); with the proviso that[3H]-triamcinolone acetonide is excluded from the combination.
 10. Amethod according to claim 9, comprising administering saidanti-inflammatory effective amount to the eye or eyes of a warm-bloodedanimal exhibiting an ophthalmic inflammatory response; to the nasalmucosa of a warm-blooded animal exhibiting a nasal inflammatoryresponse; by oral inhalation to a warm-blooded animal exhibiting anasthmatic inflammatory response; to the rectal mucosa of a warm-bloodedanimal exhibiting inflammation of the upper or lower intestine orrectum; orally to a warm-blooded animal exhibiting an inflammatoryresponse of the upper or lower intestines; to the ear or ears of awarm-blooded animal exhibiting an otic inflammatory response; byinjection into the joint or joints of a warm-blooded animal exhibitingan arthritic response; to the skin of a warm-blooded animal exhibiting adermal inflammatory response; or orally to a warm-blooded animalexhibiting an oral, gingival or throat inflammatory response.
 11. Amethod for alleviating inflammation in or on a warm-blooded animalexhibiting a topical or other localized inflammatory response, whichcomprises topically or otherwise locally administering to said animal ananti-inflammatory effective amount of a combination comprisingloteprednol etabonate and a compound having the formula:

wherein R is H or C₁-C₄ alkyl and the dotted line in ring A indicatesthat the 1,2-linkage is saturated or unsaturated, in a combinedsynergistic anti-inflammatory effective amount, the amount of thecompound of formula (IIa) being sufficient to enhance theanti-inflammatory activity or duration of action, or both, ofloteprednol etabonate, with the proviso that [3H]-triamcinoloneacetonide is excluded from the combination.
 12. A method according toclaim 11, wherein, in the compound of formula (IIa), R is H, methyl orethyl.
 13. A method according to claim 12, wherein the compound offormula (IIa) is 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylicacid or methyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.14. A method according to claim 11, wherein the molar ratio of compoundof formula (IIa) to loteprednol etabonate is from about 5:1 to about0.5:1.
 15. A method according to claim 12, wherein the molar ratio ofcompound of formula (IIa) to loteprednol etabonate is from about 5:1 toabout 0.5:1.
 16. A method according to claim 13, wherein the molar ratioof compound of formula (IIa) to loteprednol etabonate is from about 5:1to about 0.5:1.
 17. A method according to claim 11, comprisingadministering said anti-inflammatory effective amount to the eye or eyesof a warm-blooded animal exhibiting an ophthalmic inflammatory response;to the nasal mucosa of a warm-blooded animal exhibiting a nasalinflammatory response; by oral inhalation to a warm-blooded animalexhibiting an asthmatic inflammatory response; to the rectal mucosa of awarm-blooded animal exhibiting inflammation of the upper or lowerintestine or rectum; orally to a warm-blooded animal exhibiting aninflammatory response of the upper or lower intestines; to the ear orears of a warm-blooded animal exhibiting an otic inflammatory response;by injection into the joint or joints of a warm-blooded animalexhibiting an arthritic response; to the skin of a warm-blooded animalexhibiting a dermal inflammatory response; or orally to a warm-bloodedanimal exhibiting an oral, gingival or throat inflammatory response. 18.A method for alleviating inflammation in or on a warm-blooded animalexhibiting a topical or other localized inflammatory response, whichcomprises topically or otherwise locally administering to said animal ananti-inflammatory effective amount of a pharmaceutical compositioncomprising: (1) a combined synergistic anti-inflammatory effectiveamount of: (a) a compound having the formula:

wherein: R₁ is C₁-C₇ alkyl; Z is carbonyl or β-hydroxymethylene; X is Clor F; and the dotted line in ring A indicates that the 1,2-linkage issaturated or unsaturated; and (b) a compound having the formula:

wherein: R is H or C₁-C₄ alkyl; Z₁ is carbonyl or β-hydroxymethylene; X₁is —O— or —S—; R₅ is —OH, —OR₆, —OCOOR₆ or —OCOR₇ wherein R₆ is C₁-C₄alkyl and R₇ is C₁-C₄ alkyl, fluoromethyl or chloromethyl; and thedotted line is defined as above; with the proviso that when R is C₁-C₄alkyl, then R₅ is —OH; the amount of compound of formula (II) beingsufficient to enhance the anti-inflammatory activity or duration ofaction, or both, of said compound of formula (I); and (2) a non-toxic,pharmaceutically acceptable carrier therefore suitable for topical orother local application; with the proviso that [3H]-triamincoloneacetonide is excluded from the composition.
 19. A method according toclaim 18, comprising administering said anti-inflammatory effectiveamount to the eye or eyes of a warm-blooded animal exhibiting anophthalmic inflammatory response; to the nasal mucosa of a warm-bloodedanimal exhibiting a nasal inflammatory response; by oral inhalation to awarm-blooded animal exhibiting an asthmatic inflammatory response; tothe rectal mucosa of a warm-blooded animal exhibiting inflammation ofthe upper or lower intestine or rectum; orally to a warm-blooded animalexhibiting an inflammatory response of the upper or lower intestines; tothe ear or ears of a warm-blooded animal exhibiting an otic inflammatoryresponse; by injection into the joint or joints of a warm-blooded animalexhibiting an arthritic response; to the skin of a warm-blooded animalexhibiting a dermal inflammatory response; or orally to a warm-bloodedanimal exhibiting an oral, gingival or throat inflammatory response. 20.A method for alleviating inflammation in or on a warm-blooded animalexhibiting a topical or other localized inflammatory response, whichcomprises topically or otherwise locally administering to said animal ananti-inflammatory effective amount of a pharmaceutical compositioncomprising: (1) a combined synergistic anti-inflammatory effectiveamount of: (a) loteprednol etabonate; and (b) a compound having theformula:

wherein R is H or C₁-C₄ alkyl and the dotted line in ring A indicatesthat the 1,2-linkage is saturated or unsaturated, the amount of compoundof formula (IIa) being sufficient to enhance the anti-inflammatoryactivity or duration of action, or both, of loteprednol etabonate; and(2) a non-toxic, pharmaceutically acceptable carrier therefore suitablefor topical or other local application; with the proviso that[3H]-triamcinolone acetonide is excluded from the composition.
 21. Amethod according to claim 20, wherein, in the compound of formula (IIa),R is H, methyl or ethyl.
 22. A method according to claim 21, wherein thecompound of formula (IIa) is 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid or methyl11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.
 23. A methodaccording to claim 20, wherein the molar ratio of compound of formula(IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.
 24. Amethod according to claim 21, wherein the molar ratio of compound offormula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.25. A method according to claim 22, wherein the molar ratio of compoundof formula (IIa) to loteprednol etabonate is from about 5:1 to about0.5:1.
 26. A method according to claim 20, comprising administering saidanti-inflammatory effective amount to the eye or eyes of a warm-bloodedanimal exhibiting an ophthalmic inflammatory response; to the nasalmucosa of a warm-blooded animal exhibiting a nasal inflammatoryresponse; by oral inhalation to a warm-blooded animal exhibiting anasthmatic inflammatory response; to the rectal mucosa of a warm-bloodedanimal exhibiting inflammation of the upper or lower intestine orrectum; orally to a warm-blooded animal exhibiting an inflammatoryresponse of the upper or lower intestines; to the ear or ears of awarm-blooded animal exhibiting an otic inflammatory response; byinjection into the joint or joints of a warm-blooded animal exhibitingan arthritic response; to the skin of a warm-blooded animal exhibiting adermal inflammatory response; or orally to a warm-blooded animalexhibiting an oral, gingival or throat inflammatory response.